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Mammalian Germ Cells Are Determined After PGC Colonization of the Nascent Gonad SEE COMMENTARY

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Mammalian Germ Cells Are Determined After PGC Colonization of the Nascent Gonad SEE COMMENTARY Mammalian germ cells are determined after PGC colonization of the nascent gonad SEE COMMENTARY Peter K. Nichollsa, Hubert Schorlea,b, Sahin Naqvia,c, Yueh-Chiang Hua,d,e, Yuting Fana,f, Michelle A. Carmella, Ina Dobrinskig, Adrienne L. Watsonh, Daniel F. Carlsonh, Scott C. Fahrenkrugh, and David C. Pagea,c,i,1 aWhitehead Institute, Cambridge, MA 02142; bDepartment of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany; cDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; dDivision of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; eDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267; fReproductive Medicine Center, Sixth Affiliated Hospital, Sun Yat-sen University, 510655 Guangzhou, China; gDepartment of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; hRecombinetics, Inc., Saint Paul, MN 55104; and iHoward Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142 Contributed by David C. Page, October 15, 2019 (sent for review June 28, 2019; reviewed by Katherine L. Nathanson and Dustin L. Updike) Mammalian primordial germ cells (PGCs) are induced in the embry- lines in culture (9–11). It has also been suggested that pre- onic epiblast, before migrating to the nascent gonads. In fish, sumptive PGCs (labeled genetically by Prdm1-Cre) in the pos- frogs, and birds, the germline segregates even earlier, through the terior region of the embryo during allantoic elongation may action of maternally inherited germ plasm. Across vertebrates, contribute to nongametogenic lineages (12, 13). Taken together, migrating PGCs retain a broad developmental potential, regardless these observations suggest that migratory PGCs of vertebrates of whether they were induced or maternally segregated. In retain a broad developmental potential, regardless of their mode mammals, this potential is indicated by expression of pluripotency of segregation. That is, migratory PGCs, while clearly cells of the factors, and the ability to generate teratomas and pluripotent cell germline (the entire lineage from zygote to gamete), may not yet lines. How the germline loses this developmental potential re- be germ cells, which, by definition, are committed to producing mains unknown. Our genome-wide analyses of embryonic human gametes and no other cell types (14). and mouse germlines reveal a conserved transcriptional program, To better understand germline commitment in mammals, we initiated in PGCs after gonadal colonization, that differentiates examine the transition that occurs as PGCs invade the nascent germ cells from their germline precursors and from somatic line- DEVELOPMENTAL BIOLOGY ages. Through genetic studies in mice and pigs, we demonstrate gonads. We find a transcriptional program, initiated in human and that one such gonad-induced factor, the RNA-binding protein mouse PGCs after colonization of the gonad, that distinguishes DAZL, is necessary in vivo to restrict the developmental potential germ cells from their migratory germline precursors, and from of the germline; DAZL’s absence prolongs expression of a Nanog soma. Through genetic studies, we demonstrate that this program pluripotency reporter, facilitates derivation of pluripotent cell lines, is necessary for germ cell commitment in mammals. In embryonic and causes spontaneous gonadal teratomas. Based on these obser- mice deficient in one factor induced at PGC colonization—the vations in humans, mice, and pigs, we propose that germ cells are determined after gonadal colonization in mammals. We suggest Significance that germ cell determination was induced late in embryogenesis— — after organogenesis has begun in the common ancestor of all In mammals, the germline is set aside early in development for vertebrates, as in modern mammals, where this transition is in- the later production of the gametes, either eggs or sperm. It duced by somatic cells of the gonad. We suggest that failure of remains unknown when, and how, the precursor cells (termed this process of germ cell determination likely accounts for the primordial germ cells [PGCs]) become committed to produce origin of human testis cancer. only gametes, and no other cell type. We identify an embryonic transition occurring late in development, after PGCs colonize germ cell | commitment | teratoma | pluripotency | Dazl the nascent gonad, that serves to commit these cells to produce only gametes. Our findings have broad implications for the uring embryogenesis, cells segregate into germline and so- origin of germ cell tumors in humans, and for the stepwise Dmatic lineages. In mammals, this split is first evident around commitment of the germline in mammals and other vertebrates. the time of gastrulation, when intercellular signaling induces the formation of primordial germ cells (PGCs) (1, 2). Comparative Author contributions: P.K.N. and D.C.P. conceptualized the project; P.K.N., H.S., S.N., I.D., studies reveal that an inductive method of germline segregation A.L.W., D.F.C., S.C.F., and D.C.P. designed research; P.K.N., H.S., S.N., Y.-C.H., Y.F., M.A.C., I.D., A.L.W., and D.F.C. performed research; P.K.N., Y.-C.H., M.A.C., I.D., A.L.W., D.F.C., and likely existed in the common ancestor of all vertebrates (3). However, S.C.F. contributed new reagents/analytic tools; P.K.N., H.S., S.N., Y.-C.H., Y.F., I.D., A.L.W., some vertebrates, such as fish, frogs, and birds, have acquired a dif- and D.F.C. analyzed data; and P.K.N. and D.C.P. wrote the paper. ferent approach to germline segregation. It occurs much earlier in these Reviewers: K.L.N., Raymond and Ruth Perelman School of Medicine at the University of species—during the first cell divisions of the zygote—through the Pennsylvania; and D.L.U., Mount Desert Island Biological Laboratory. action of maternally supplied RNAs known as germ plasm (4). Competing interest statement: A.L.W., D.F.C., and S.C.F. are employees and shareholders Despite these different strategies for PGC formation, emerg- of Recombinetics Inc. I.D. is a member of the scientific advisory board of Recombinetics ing evidence suggests that migratory PGCs of nonmammalian Inc. The remaining authors have declared that no competing interests exist. vertebrates remain developmentally uncommitted to gametogen- Published under the PNAS license. esis, retaining the capacity for somatic differentiation. In frogs, Data deposition: Data generated using the Mouse Diversity Genotyping Array (Thermo Fisher Scientific) for the SNP genotyping of 129S2 and 129S4 substrains have been de- PGCs arising via germ plasm readily differentiate into somatic posited at the Gene Expression Omnibus under accession no. GSE87771. Data generated cells when transplanted into host embryos (5). Similarly, in fish, from control and Dazl-deficient germ line cells at E10.3 and E11.5 have been deposited mismigrated PGCs readily adopt somatic fates if depleted of Dnd1 under the Sequence Read Archive BioProject accession no. PRJNA434733. (6). In salamanders, where PGCs arise through inductive processes, See Commentary on page 25374. irreversible commitment of the germline occurs late in develop- 1To whom correspondence may be addressed. Email: [email protected]. ment, long after gastrulation is complete and somatic lineages are This article contains supporting information online at https://www.pnas.org/lookup/suppl/ established (7). In mammals, migratory PGCs can form teratomas if doi:10.1073/pnas.1910733116/-/DCSupplemental. transplanted to ectopic sites (8) and give rise to pluripotent cell First published November 21, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1910733116 PNAS | December 17, 2019 | vol. 116 | no. 51 | 25677–25687 Downloaded by guest on September 30, 2021 RNA-binding protein Dazl—the germline remains developmentally embryonic stem [ES] cells) (17–19) (SI Appendix, Fig. S3). uncommitted, retaining expression of a network of pluripotency [Pluripotency factors are similarly expressed in migratory PGCs factors, the capacity for pluripotent cell line derivation, and the of fish and birds (20, 21).] Further, in humans and mice of both potential to form gonadal teratomas in mice and pigs. sexes, these pluripotency factors are markedly down-regulated after PGC colonization and induction of the germ cell-defining Results program of gene expression (SI Appendix,Fig.S3). Might activa- Germ Cell Determinants of Nonmammalian Vertebrates Are Expressed tion of this program be necessary to down-regulate pluripotency in Mice and Humans upon PGC Colonization of the Nascent Gonads. We factors and restrict the developmental potential of the germline? searched for changes in gene expression that accompany PGC colonization of gonads in mammals. To this end, we reanalyzed Expression of Pluripotency Factors, and the Capacity for Deriving published transcriptomes of migratory and gonadal germline cells Pluripotent Cell Lines, Are Prolonged in Dazl-Deficient Mice. We from mouse (15) and human (16) embryos. Our analyses in mice considered whether the program of gene expression induced identified 74 genes whose expression increased robustly after after PGCs colonize the gonads functions in germ cell commit- PGCs colonized the gonads (fold change of >4 [presented as log2 ment. Evidence from a range of vertebrates suggests that DAZL, transformed] from E9.5 to E11.5, false discovery rate (FDR) < encoding an RNA-binding protein, might contribute to this 0.05; Fig. 1A and Datasets S1 and S2). To determine whether this function. For example, DAZL orthologs function in the germ program of gene expression is similarly induced in human em- plasm of fish (22, 23), frogs (24, 25), and birds (26). In C57BL/6 bryos, we reanalyzed the transcriptomes of single cells within a mice (B6), Dazl is necessary for licensing—the acquisition of comparable developmental window (XY: weeks 4 to 9; XX: weeks meiotic and gametogenic competence—after PGCs colonize the 5to7and8;Dataset S3 and SI Appendix,Fig.S1). Of the 74 genes gonads (27), and studies of mouse and human ES cells have induced in mice, 44 have one-to-one orthologs in humans.
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